Gadd45b is required in part for the anti-obesity effect of constitutive androstane receptor (CAR)
| Autor: | Wen Xie, Chaohui Yu, Meishu Xu, Xinran Cai, Ye Feng |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
medicine.medical_specialty
Adipose tissue Xenobiotics 03 medical and health sciences 0302 clinical medicine Internal medicine Coactivator Constitutive androstane receptor medicine Obesity General Pharmacology Toxicology and Pharmaceutics Receptor Glucogenogenesis 030304 developmental biology 0303 health sciences Chemistry Lipogenesis Diabetes lcsh:RM1-950 CAR Endocrinology lcsh:Therapeutics. Pharmacology Nuclear receptor 030220 oncology & carcinogenesis Knockout mouse Original Article GADD45B Gadd45b |
| Zdroj: | Acta Pharmaceutica Sinica B, Vol 11, Iss 2, Pp 434-441 (2021) Acta Pharmaceutica Sinica. B |
| ISSN: | 2211-3835 |
| Popis: | Crosstalk between xenobiotic metabolism and energy metabolism in the liver has provided a potential opportunity to target xenobiotic receptors to treat metabolic diseases. Activation of constitutive androstane receptor (CAR), a xenobiotic-sensing nuclear receptor, has been shown to inhibit obesity, suppress hepatic gluconeogenesis, and ameliorate hyperglycemia in rodent models of obesity and type 2 diabetes. However, the underlying molecular mechanism remains to be defined. The growth arrest and DNA damage-inducible gene 45b (Gadd45b), a well-known anti-apoptotic factor, has been shown to be an inducible coactivator of CAR in promoting rapid liver growth. It is unknown whether the effect of CAR on energy metabolism depends on GADD45B. In the present study and by using a high fat diet (HFD)-induced obesity model, we show that reduced body weight gain and improved insulin sensitivity by the CAR agonist 1,4-bis[2-(3,5-dichloropyridyloxy)] benzene (TCPOBOP) were markedly blunted in Gadd45b knockout mice. Mechanistically, the TCPOBOP-responsive inhibition of hepatic lipogenesis, gluconeogenesis, and adipose inflammation observed in wild type mice were largely abolished in Gadd45b knockout mice. We conclude that Gadd45b is required in part for the metabolic benefits of CAR activation. Graphical abstract Activation of xenobiotic receptor constitutive androstane receptor (CAR) by its agonist such as TCPOBOP conveys benefits for obesity and diabetes. In this study, it showes that anti-apoptotic factor GADD45B, a coactivator of CAR, is in part required for the anti-obesity effects of CAR activation. Inhibition of hepatic lipogenesis and gluconeogenesis and adipose inflammation by TCPOBOP was largely abolished in mice in the absence of GADD45B.Image 1 |
| Databáze: | OpenAIRE |
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